Abstract
The 22q11 deletion syndrome (22q11DS) is a developmental syndrome comprising of heart, palate, thymus and parathyroid glands defects. Individuals with 22q11DS usually carry a 1.5- to 3-Mb heterozygous deletion on chromosome 22q11.2. However, there are many patients with features of 22q11DS without a known cause from conventional karyotype and FISH analysis. Six patients with features of 22q11DS, a normal chromosomal and FISH 22q11 analysis, were selected for investigation by microarray genomic comparative hybridisation (array CGH). Array-CGH is a powerful technology enabling detection of submicroscopic chromosome duplications and deletions by comparing a differentially labelled test sample to a control. The samples are co-hybridised to a microarray containing genomic clones and the resulting ratio of fluorescence intensities on each array element is proportional to the DNA copy number difference. No chromosomal changes were detected by hybridisation to a high resolution array representing chromosome 22q. However, one patient was found to have a 6-Mb deletion on 5q11.2 detected by a whole genome 1-Mb array. This deletion was confirmed with fluorescence in-situ hybridisation (FISH) and microsatellite marker analysis. It is the first deletion described in this region. The patient had tetralogy of Fallot, a bifid uvula and velopharyngeal insufficiency, short stature, learning and behavioural difficulties. This case shows the increased sensitivity of array CGH over detailed karyotype analysis for detection of chromosomal changes. It is anticipated that array CGH will improve the clinician’s capacity to diagnose congenital syndromes with an unknown aetiology.
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Adham IM, Sallam MA, Steding G, Korabiowska M, Brinck U, Hoyer-Fender S, Oh C, Engel W (2003) Disruption of the pelota gene causes early embryonic lethality and defects in cell cycle progression. Mol Cell Biol 23:1470–1476
Bachiller D, Klingensmith J, Shneyder N, Tran U, Anderson R, Rossant J, De Robertis EM (2003) The role of chordin/Bmp signals in mammalian pharyngeal development and DiGeorge syndrome. Development 130:3567–3578
Bailey JA, Gu Z, Clark RA, Reinert K, Samonte RV, Schwartz S, Adams MD, Myers EW, Li PW, Eichler EE (2002) Recent segmental duplications in the human genome. Science 297:1003–1007
Bijnens AP, Gils A, Jutten B, Faber BC, Heeneman S, Kitslaar PJ, Tordoir JH, de Vries CJ, Kroon AA, Daemen MJ, Cleutjens KB (2003) Vasculin, a novel vascular protein differentially expressed in human atherogenesis. Blood 102:2803–2810
Brewer C, Holloway S, Zawalnyski P, Schinzel A, FitzPatrick D (1998) A chromosomal deletion map of human malformations. Am J Hum Genet 63:1153–1159
Buckley PG, Mantripragada KK, Benetkiewicz M, Tapia-Paez I, Diaz DS, Rosenquist M, Ali H, Jarbo C, De Bustos C, Hirvela C, Sinder WB, Fransson I, Thyr C, Johnsson BI, Bruder CE, Menzel U, Hergersberg M, Mandahl N, Blennow E, Wedell A, Beare DM, Collins JE, Dunham I, Albertson D, Pinkel D, Bastian BC, Faruqi AF, Lasken RS, Ichimura K, Collins VP, Dumanski JP (2002) A full-coverage, high-resolution human chromosome 22 genomic microarray for clinical and research applications. Hum Mol Genet 11:3221–3229
Cai CL, Liang X, Shi Y, Chu PH, Pfaff SL, Chen J, Evans S (2003) Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell 5:877–889
Carey AH, Kelly D, Halford S, Wadey R, Wilson D, Goodship J, Burn J, Paul T, Sharkey A, Dumanski J, Nordenskjold M, Williamson R, Scambler PJ (1992) Molecular genetic study of the frequency of monosomy 22q11 in DiGeorge syndrome. Am J Hum Genet 51:964–970
Chen J, Diacovo TG, Grenache DG, Santoro SA, Zutter MM (2002) The alpha(2) integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis. Am J Pathol 161:337–344
Feijen A, Goumans MJ, van den Eijnden-van Raaij AJ (1994) Expression of activin subunits, activin receptors and follistatin in postimplantation mouse embryos suggests specific developmental functions for different activins. Development 120:3621–3637
Fiegler H, Carr P, Douglas EJ, Burford DC, Hunt S, Scott CE, Smith J, Vetrie D, Gorman P, Tomlinson IP, Carter NP (2003) DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones. Genes Chromosomes Cancer 36:361–374
Gong W, Gottlieb S, Collins J, Blescia A, Dietz H, Goldmuntz E, McDonald-McGinn DM, Zackai EH, Emanuel BS, Driscoll DA, Budarf ML (2001) Mutation analysis of TBX1 in non-deleted patients with features of DGS/VCFS or isolated cardiovascular defects. J Med Genet 38:E45
Hemmati-Brivanlou A, Kelly OG, Melton DA (1994) Follistatin, an antagonist of activin, is expressed in the Spemann organizer and displays direct neuralizing activity. Cell 77:283–295
Iemura S, Yamamoto TS, Takagi C, Uchiyama H, Natsume T, Shimasaki S, Sugino H, Ueno N (1998) Direct binding of follistatin to a complex of bone-morphogenetic protein and its receptor inhibits ventral and epidermal cell fates in early Xenopus embryo. Proc Natl Acad Sci USA 95:9337–9342
Jain AN, Tokuyasu TA, Snijders AM, Segraves R, Albertson DG, Pinkel D (2002) Fully automatic quantification of microarray image data. Genome Res 12:325–332
Kallioniemi A, Kallioniemi OP, Sudar D, Rutovitz D, Gray JW, Waldman F, Pinkel D (1992) Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258:818–821
Kirchhoff M, Rose H, Lundsteen C (2001) High resolution comparative genomic hybridisation in clinical cytogenetics. J Med Genet 38:740–744
Lee HJ, Adham IM, Schwarz G, Kneussel M, Sass JO, Engel W, Reiss J (2002) Molybdenum cofactor-deficient mice resemble the phenotype of human patients. Hum Mol Genet 11:3309–3317
Matzuk MM, Lu N, Vogel H, Sellheyer K, Roop DR, Bradley A (1995) Multiple defects and perinatal death in mice deficient in follistatin. Nature 374:360–363
Monni O, Barlund M, Mousses S, Kononen J, Sauter G, Heiskanen M, Paavola P, Avela K, Chen Y, Bittner ML, Kallioniemi A (2001) Comprehensive copy number and gene expression profiling of the 17q23 amplicon in human breast cancer. Proc Natl Acad Sci USA 98:5711–5716
Nakamura T, Takio K, Eto Y, Shibai H, Titani K, Sugino H (1990) Activin-binding protein from rat ovary is follistatin. Science 247:836–838
Nilsen H, Stamp G, Andersen S, Hrivnak G, Krokan HE, Lindahl T, Barnes DE (2003) Gene-targeted mice lacking the Ung uracil-DNA glycosylase develop B-cell lymphomas. Oncogene 22:5381–5386
Piccolo S, Sasai Y, Lu B, De Robertis EM (1996) Dorsoventral patterning in Xenopus: inhibition of ventral signals by direct binding of chordin to BMP-4. Cell 86:589–598
Pinkel D, Landegent J, Collins C, Fuscoe J, Segraves R, Lucas J, Gray J (1988) Fluorescence in situ hybridization with human chromosome-specific libraries: detection of trisomy 21 and translocations of chromosome 4. Proc Natl Acad Sci USA 85:9138–9142
Pinkel D, Segraves R, Sudar D, Clark S, Poole I, Kowbel D, Collins C, Kuo WL, Chen C, Zhai Y, Dairkee SH, Ljung BM, Gray JW, Albertson DG (1998) High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet 20:207–211
Pollack JR, Sorlie T, Perou CM, Rees CA, Jeffrey SS, Lonning PE, Tibshirani R, Botstein D, Borresen-Dale AL, Brown PO (2002) Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors. Proc Natl Acad Sci USA 99:12963–12968
Redon R, Hussenet T, Bour G, Caulee K, Jost B, Muller D, Abecassis J, du Manoir S (2002) Amplicon mapping and transcriptional analysis pinpoint cyclin L as a candidate oncogene in head and neck cancer. Cancer Res 62:6211–6217
Reiss J, Dorche C, Stallmeyer B, Mendel RR, Cohen N, Zabot MT (1999) Human molybdopterin synthase gene: genomic structure and mutations in molybdenum cofactor deficiency type B. Am J Hum Genet 64:706–711
Scambler PJ (2000) The 22q11 deletion syndromes. Hum Mol Genet 9:2421–2426
Shaw-Smith C, Redon R, Rickman L, Rio M, Willatt L, Fiegler H, Firth H, Sanlaville D, Winter R, Colleaux L, Bobrow M, Carter NP (2004) Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features. J Med Genet 41:241–248
Shimomura H, Sanke T, Hanabusa T, Tsunoda K, Furuta H, Nanjo K (2000) Nonsense mutation of islet-1 gene (Q310X) found in a type 2 diabetic patient with a strong family history. Diabetes 49:1597–1600
Solinas-Toldo S, Lampel S, Stilgenbauer S, Nickolenko J, Benner A, Dohner H, Cremer T, Lichter P (1997) Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes Chromosomes Cancer 20:399–407
Tanaka SS, Toyooka Y, Akasu R, Katoh-Fukui Y, Nakahara Y, Suzuki R, Yokoyama M, Noce T (2000) The mouse homolog of Drosophila Vasa is required for the development of male germ cells. Genes Dev 14:841–853
van den Heuvel L, Ruitenbeek W, Smeets R, Gelman-Kohan Z, Elpeleg O, Loeffen J, Trijbels F, Mariman E, de Bruijn D, Smeitink J (1998) Demonstration of a new pathogenic mutation in human complex I deficiency: a 5-bp duplication in the nuclear gene encoding the 18-kD (AQDQ) subunit. Am J Hum Genet 62:262–268
Veltman JA, Fridlyand J, Pejavar S, Olshen AB, Korkola JE, DeVries S, Carroll P, Kuo WL, Pinkel D, Albertson D, Cordon-Cardo C, Jain AN, Waldman FM (2003) Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors. Cancer Res 63:2872–2880
Veltman JA, Schoenmakers EF, Eussen BH, Janssen I, Merkx G, van Cleef B, van Ravenswaaij CM, Brunner HG, Smeets D, Van Kessel AG (2002) High-throughput analysis of subtelomeric chromosome rearrangements by use of array-based comparative genomic hybridization. Am J Hum Genet 70:1269–1276
Vissers LE, de Vries BB, Osoegawa K, Janssen IM, Feuth T, Choy CO, Straatman H, van der Vliet W, Huys EH, Van Rijk A, Smeets D, Ravenswaaij-Arts CM, Knoers NV, van der Burgt I, de Jong PJ, Brunner HG, van Kessel AG, Schoenmakers EF, Veltman JA (2003) Array-based comparative genomic hybridization for the genomewide detection of submicroscopic chromosomal abnormalities. Am J Hum Genet 73:1261–1270
Vitelli F, Taddei I, Morishima M, Meyers EN, Lindsay EA, Baldini A (2002) A genetic link between Tbx1 and fibroblast growth factor signaling. Development 129:4605–4611
Wessendorf S, Schwaenen C, Kohlhammer H, Kienle D, Wrobel G, Barth TF, Nessling M, Moller P, Dohner H, Lichter P, Bentz M (2003) Hidden gene amplifications in aggressive B-cell non-Hodgkin lymphomas detected by microarray-based comparative genomic hybridization. Oncogene 22:1425–1429
Wilhelm M, Veltman JA, Olshen AB, Jain AN, Moore DH, Presti JC Jr, Kovacs G, Waldman FM (2002) Array-based comparative genomic hybridization for the differential diagnosis of renal cell cancer. Cancer Res 62:957–960
Yagi H, Furutani Y, Hamada H, Sasaki T, Asakawa S, Minoshima S, Ichida F, Joo K, Kimura M, Imamura S, Kamatani N, Momma K, Takao A, Nakazawa M, Shimizu N, Matsuoka R (2003) Role of TBX1 in human del22q11.2 syndrome. Lancet 362:1366–1373
Yoshida K, Taga T, Saito M, Suematsu S, Kumanogoh A, Tanaka T, Fujiwara H, Hirata M, Yamagami T, Nakahata T, Hirabayashi T, Yoneda Y, Tanaka K, Wang WZ, Mori C, Shiota K, Yoshida N, Kishimoto T (1996) Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. Proc Natl Acad Sci USA 93:407–411
Yu W, Ballif BC, Kashork CD, Heilstedt HA, Howard LA, Cai WW, White LD, Liu W, Beaudet AL, Bejjani BA, Shaw CA, Shaffer LG (2003) Development of a comparative genomic hybridization microarray and demonstration of its utility with 25 well-characterized 1p36 deletions. Hum Mol Genet 12:2145–2152
Yujiri T, Sather S, Fanger GR, Johnson GL (1998) Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption. Science 282:1911–1914
Zemmyo M, Meharra EJ, Kuhn K, Creighton-Achermann L, Lotz M (2003) Accelerated, aging-dependent development of osteoarthritis in alpha1 integrin-deficient mice. Arthritis Rheum 48:2873–2880
Acknowledgements
We thank Heike Fiegler and Chiara Bacchelli for technical support and the Wellcome Trust Sanger Institute Microarray Core Facility for printing the microarrays. This work is funded by the Wellcome Trust.
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Prescott, K., Woodfine, K., Stubbs, P. et al. A novel 5q11.2 deletion detected by microarray comparative genomic hybridisation in a child referred as a case of suspected 22q11 deletion syndrome. Hum Genet 116, 83–90 (2005). https://doi.org/10.1007/s00439-004-1195-6
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DOI: https://doi.org/10.1007/s00439-004-1195-6